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Long-term remission of hormone receptor-positive/HER2-positive metastatic breast cancer due to combined treatment with everolimus/trastuzumab/exemestane: A case report
Abstract
The present case report describes a postmenopausal patient with hormone receptor (HR)⁺/human epidermal growth factor receptor 2 (HER2)⁺ metastatic breast cancer, who experienced progression of disease in bilateral lungs, lymph nodes and the liver under previous endocrine therapy and trastuzumab. Following the failure of two lines of endocrine-based treatment, the patient was administered the combined treatment of everolimus, trastuzumab and exemestane following surgical resection of the liver metastasis. A durable partial remission was achieved, which has continued for >27 months. This prominent clinical outcome in this patient demonstrates that the combined administration of endocrine therapy, trastuzumab and everolimus is clinically effective, and may induce long-term remission in patients with HR⁺/HER2⁺ metastatic breast cancer.
... Severe side effects and poor delivery efficiency of chemotherapy agents severely limit their therapeutic efficacy [6][7][8][9][10] . With the changes in the understanding of biological behaviors of breast cancer and the renewal of treatment concepts, the treatment of cancer has entered the era of comprehensive treatment, forming a treatment mode that emphasizes combination therapy of breast cancer, such as magnetic hyperthermia and photodynamic therapy [11][12][13][14][15] . ...
To effectively inhibit the growth of breast cancer cells (MDA-MB-231 cells) by the combination method of chemotherapy and magnetic hyperthermia, we fabricated a biomimetic drug delivery (CSiFePNs) system composed of mesoporous silica nanoparticles (MSNs) containing superparamagnetic ferroferric oxide and Paclitaxel (PTX) coated with MDA-MB-231 cell membranes (CMs). In the in vitro cytotoxicity tests, the MDA-MB-231 cells incubated with CSiFePNs obtained IC50 value of 0.8 μgL−1, 3.5-fold higher than that of SiFePNs. The combination method of chemotherapy and magnetic hyperthermia can effectively inhibit the growth of MDA-MB-231 cells.
With increasing incidence and mortality, cancer is the leading cause of death in China and is a major public health problem. Because of China's massive population (1.37 billion), previous national incidence and mortality estimates have been limited to small samples of the population using data from the 1990s or based on a specific year. With high-quality data from an additional number of population-based registries now available through the National Central Cancer Registry of China, the authors analyzed data from 72 local, population-based cancer registries (2009-2011), representing 6.5% of the population, to estimate the number of new cases and cancer deaths for 2015. Data from 22 registries were used for trend analyses (2000-2011). The results indicated that an estimated 4292,000 new cancer cases and 2814,000 cancer deaths would occur in China in 2015, with lung cancer being the most common incident cancer and the leading cause of cancer death. Stomach, esophageal, and liver cancers were also commonly diagnosed and were identified as leading causes of cancer death. Residents of rural areas had significantly higher age-standardized (Segi population) incidence and mortality rates for all cancers combined than urban residents (213.6 per 100,000 vs 191.5 per 100,000 for incidence; 149.0 per 100,000 vs 109.5 per 100,000 for mortality, respectively). For all cancers combined, the incidence rates were stable during 2000 through 2011 for males (+0.2% per year; P = .1), whereas they increased significantly (+2.2% per year; P < .05) among females. In contrast, the mortality rates since 2006 have decreased significantly for both males (−1.4% per year; P < .05) and females (−1.1% per year; P < .05). Many of the estimated cancer cases and deaths can be prevented through reducing the prevalence of risk factors, while increasing the effectiveness of clinical care delivery, particularly for those living in rural areas and in disadvantaged populations. CA Cancer J Clin 2016.
Resistance to endocrine therapies in hormone receptor (HR)-positive breast cancer is a significant clinical problem for a considerable number of patients. The oncogenic transcription factor c-MYC (hereafter referred to as MYC), which regulates glutamine metabolism in cancer cells, has been linked to endocrine resistance. We were interested in whether MYC-mediated glutamine metabolism is also associated with aromatase inhibitor (AI) resistant breast cancer. We studied the expression and regulation of MYC and the effects of inhibition of MYC expression in both AI sensitive and resistant breast cancer cells. Considering the role of MYC in glutamine metabolism, we evaluated the contribution of glutamine to the proliferation of AI sensitive and resistant cells, and performed RNA-sequencing to investigate mechanisms of MYC-mediated glutamine utilization in AI resistance. We found that glutamine metabolism was independent of estrogen but still required ER in AI resistant breast cancer cells. The expression of MYC oncogene was up-regulated through the cross-talk between estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) in AI resistant breast cancer cells. Moreover, the glutamine transporter solute carrier family (SLC) 1A5 was significantly up-regulated in AI resistant breast cancer cells. ER down-regulator fulvestrant inhibited MYC, SLC1A5, glutaminase (GLS) and glutamine consumption in AI resistant breast cancer cells. Inhibition of MYC, SLC1A5 and GLS decreased AI resistant breast cancer cell proliferation. Our study has uncovered that MYC expression is up-regulated by the cross-talk between ER and HER2 in AI resistant breast cancer cells. MYC-mediated glutamine metabolism is associated with AI resistance of breast cancer.
Copyright © 2015. Published by Elsevier Ltd.
Everolimus (RAD001, Afinitor(®)) is an oral, selective mTOR inhibitor recently approved by the US-FDA in combination with exemestane for treatment of hormone receptor positive advanced breast cancer. To date, no molecular predictors of response to everolimus in breast cancer have been identified. We hypothesized predictive markers could be identified using preclinical models. Using a molecularly characterized panel of human breast cancer and immortalized breast epithelial cell lines, we determined sensitivity to everolimus alone or in combination with ER- or HER2- targeted therapy. Gene expression microarrays and comparative genomic hybridization were performed on the cell lines to identify predictors of response to everolimus. Among 13 everolimus-sensitive cell lines, 10/13(77 %) were luminal, while in 26 resistant cell lines, 16/26(62 %) were non-luminal, and 10/26(38 %) were luminal. Only 3/24 non-luminal lines were sensitive, two of which were HER2+. Everolimus enhanced the anti-proliferative effect of both tamoxifen (TAM) and fulvestrant (FUL) in ER+ breast cancer cell lines, as well as trastuzumab in HER2+ cell lines. Everolimus + FUL but not everolimus + TAM reversed acquired resistance to TAM. Everolimus inhibited mTOR in tested cell lines by decreasing S6 phosphorylation, mediating its anti-proliferative effect by G0/G1 cell cycle arrest and induction of apoptosis. Chromosomal amplifications of AURKA (p value = 0.04) and HER2 (p value = 0.03) were each associated with increased sensitivity to everolimus. Transcript expression microarrays identified GSK3A, PIK3R3, KLF8, and MAPK10 among the genes overexpressed in sensitive luminal lines, while PGP, RPL38, GPT, and GFAP were among the genes overexpressed in resistant luminal cell lines. These preclinical in vitro data provide further support for continued clinical development of everolimus in luminal (ER+ or HER2+) breast cancer in combination with targeted therapies. We identified several potential molecular markers associated with response to everolimus that will require validation in clinical material.
Everolimus, a mammalian target of Rapamycin inhibitor, has recently been approved for the treatment of metastatic estrogen receptor-positive breast cancer, in combination with exemestane at a daily dose of 10mg. In the literature, few cases of acute kidney injury have been reported related to everolimus use, but none of them in a patient with breast cancer as we report here. Our case report of acute kidney injury demonstrates the potential nephrotoxic effects of everolimus therapy, necessitating close monitoring of renal function prior to, during and after discontinuation of the drug.
We report the first published case of acute kidney injury shortly after initiation of exemestane and everolimus for metastatic breast cancer resistant to letrozole in a 69-year-old Caucasian woman, initially treated for a stage IIB estrogen receptor-positive breast cancer in 1997. Within 2 weeks of therapy, she developed grade 1 to 2 diarrhea, lower extremity edema, lethargy, and anorexia. After 4 weeks of therapy, her blood pressure was 85/59mmHg and she lost 4kg bodyweight. Her serum creatinine was 3.34mg/dL. Everolimus was stopped, and she was hospitalized for rehydration. Her serum creatinine levels peaked at 8.85mg/dL 8 days after treatment discontinuation, with a calculated creatinine clearance of 7mL/minute. Dialysis was not required. A month later, her serum creatinine levels slowly dropped to 2.26mg/dL but did not return to baseline. No re-challenge of everolimus was attempted.
Extreme vigilance should be used when prescribing everolimus for metastatic breast cancer. Although the exact cause of acute kidney injury in our case is unknown, dehydration must be avoided and renal function closely monitored after initiating therapy. Spontaneous recovery after drug discontinuation is possible.
The frequent alterations of the PI3K/Akt/mTOR-growth signaling pathway are proposed mechanisms for resistance to endocrine therapy in breast cancer, partly through regulation of estrogen receptor α (ER) activity. Reliable biomarkers for treatment prediction are required for improved individualized treatment. We performed a retrospective immunohistochemical analysis of primary tumors from 912 postmenopausal patients with node-negative breast cancer, randomized to either tamoxifen or no adjuvant treatment. Phosphorylated (p) Akt-serine (s) 473, p-mTOR-s2448, and ER phosphorylations-s167 and -s305 were evaluated as potential biomarkers of prognosis and tamoxifen treatment efficacy. High expression of p-mTOR indicated a reduced response to tamoxifen, most pronounced in the ER+/progesterone receptor (PgR) + subgroup (tamoxifen vs. no tamoxifen: hazard ratio (HR), 0.86; 95 % confidence interval (CI), 0.31–2.38; P = 0.78), whereas low p-mTOR expression predicted tamoxifen benefit (HR, 0.29; 95 % CI, 0.18–0.49; P = 0.000002). In addition, nuclear p-Akt-s473 as well as p-ER at -s167 and/or -s305 showed interaction with tamoxifen efficacy with borderline statistical significance. A combination score of positive pathway markers including p-Akt, p-mTOR, and p-ER showed significant association with tamoxifen benefit (test for interaction; P = 0.029). Cross-talk between growth signaling pathways and ER-signaling has been proposed to affect tamoxifen response in hormone receptor-positive breast cancer. The results support this hypothesis, as an overactive pathway was significantly associated with reduced response to tamoxifen. A clinical pre-treatment test for cross-talk markers would be a step toward individualized adjuvant endocrine treatment with or without the addition of PI3K/Akt/mTOR pathway inhibitors.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-012-2376-y) contains supplementary material, which is available to authorized users.
Cross-talk between signal transduction pathways likely contributes to hormone resistance in metastatic breast cancer (mBC). Everolimus, an oral inhibitor of the mammalian target of rapamycin, has restored sensitivity in endocrine-resistance models and shown anticancer activity in early-phase mBC clinical trials. This analysis evaluated efficacy and safety of everolimus in combination with tamoxifen in patients with mBC resistant to aromatase inhibitors (AIs).
This open-label, phase II study randomly assigned postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative, AI-resistant mBC to tamoxifen 20 mg/d plus everolimus 10 mg/d (n = 54) or tamoxifen 20 mg/d alone (n = 57). Randomization was stratified by primary and secondary hormone resistance. Primary end point was clinical benefit rate (CBR), defined as the percentage of all patients with a complete or partial response or stable disease at 6 months. No formal statistical comparison between groups was planned.
The 6-month CBR was 61% (95% CI, 47 to 74) with tamoxifen plus everolimus and 42% (95% CI, 29 to 56) with tamoxifen alone. Time to progression (TTP) increased from 4.5 months with tamoxifen alone to 8.6 months with tamoxifen plus everolimus, corresponding to a 46% reduction in risk of progression with the combination (hazard ratio [HR], 0.54; 95% CI, 0.36 to 0.81). Risk of death was reduced by 55% with tamoxifen plus everolimus versus tamoxifen alone (HR, 0.45; 95% CI, 0.24 to 0.81). The main toxicities associated with tamoxifen plus everolimus were fatigue (72% v 53% with tamoxifen alone), stomatitis (56% v 7%), rash (44% v 7%), anorexia (43% v 18%), and diarrhea (39% v 11%).
This study suggests that tamoxifen plus everolimus increased CBR, TTP, and overall survival compared with tamoxifen alone in postmenopausal women with AI-resistant mBC.
The oncologic benefit of resecting liver metastases in patients with breast cancer is unclear. This study was performed to identify predictors of survival after hepatectomy.
Between 1997 and 2010, 86 patients underwent resection of breast cancer liver metastases. Clinicopathologic characteristics of the primary breast neoplasm, timing of metastasis development, and treatment were recorded. Response to prehepatectomy chemotherapy was evaluated according to Response Criteria in Solid Tumors criteria, and the best response to chemotherapy during treatment and the response immediately before hepatectomy were noted. Univariate and multivariate analyses were performed to identify predictors of disease-free survival and overall survival.
Fifty-nine patients (69%) had estrogen receptor- or progesterone receptor- positive primary breast neoplasms. Fifty-three patients (62%) had a solitary breast cancer liver metastasis, and 73 (85%) had breast cancer liver metastases ≤5 cm. Sixty-five patients (76%) received prehepatectomy hormonal and/or chemotherapy. Four patients (6%) had progressive disease as the best response, and 19 patients (30%) had progressive disease before hepatectomy (P < .001). Seventy percent of patients who received preoperative chemotherapy or hormonal therapy had either response or stable disease immediately before hepatectomy. No postoperative deaths were observed. At a 62-month median follow-up, the disease-free survival and overall survival were 14 and 57 months, respectively. On univariate analysis, estrogen receptor/progesterone receptor status of the primary breast neoplasm, best radiographic response, and preoperative radiographic response were associated with overall survival. On multivariate analysis, estrogen receptor-negative primary breast disease (P = .009; hazard ratio, 3.3; 95% confidence interval, 1.4-8.2) and preoperative progressive disease (P = .003; hazard ratio, 3.8; 95% confidence interval, 1.6-9.2) were associated with decreased overall survival.
Resection of breast cancer liver metastases in patients with estrogen receptor-positive disease that is responding to chemotherapy is associated with improved survival. The timing of operative intervention may be critical; resection before progression is associated with a better outcome.
Resistance to endocrine therapy in breast cancer is associated with activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway. In early studies, the mTOR inhibitor everolimus added to endocrine therapy showed antitumor activity.
In this phase 3, randomized trial, we compared everolimus and exemestane versus exemestane and placebo (randomly assigned in a 2:1 ratio) in 724 patients with hormone-receptor-positive advanced breast cancer who had recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting or to treat advanced disease (or both). The primary end point was progression-free survival. Secondary end points included survival, response rate, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 359 progression-free survival events were observed.
Baseline characteristics were well balanced between the two study groups. The median age was 62 years, 56% had visceral involvement, and 84% had hormone-sensitive disease. Previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse events were stomatitis (8% in the everolimus-plus-exemestane group vs. 1% in the placebo-plus-exemestane group), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%). At the interim analysis, median progression-free survival was 6.9 months with everolimus plus exemestane and 2.8 months with placebo plus exemestane, according to assessments by local investigators (hazard ratio for progression or death, 0.43; 95% confidence interval [CI], 0.35 to 0.54; P<0.001). Median progression-free survival was 10.6 months and 4.1 months, respectively, according to central assessment (hazard ratio, 0.36; 95% CI, 0.27 to 0.47; P<0.001).
Everolimus combined with an aromatase inhibitor improved progression-free survival in patients with hormone-receptor-positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. (Funded by Novartis; BOLERO-2 ClinicalTrials.gov number, NCT00863655.).
The eLEcTRA trial compared efficacy and safety of letrozole combined with trastuzumab to letrozole alone in patients with HER2 and hormone receptor (HR) positive metastatic breast cancer (MBC). Patients were randomized to either letrozole alone (arm A, n = 31) or letrozole plus trastuzumab (arm B, n = 26) as first-line treatment. Additional 35 patients with HER2 negative and HR positive tumors received letrozole alone (arm C). Median time to progression in arm A was 3.3 months compared to 14.1 months in arm B (hazard ratio 0.67; p = 0.23) and 15.2 months in arm C (hazard ratio 0.71; p = 0.03). Clinical benefit rate was 39% for arm A compared to 65% in arm B (odds ratio 2.99, 95% CI 1.01-8.84) and 77% in arm C (odds ratio 5.34, 95% CI 1.83-15.58). The eLEcTRA trial showed that the combination of letrozole and trastuzumab is a safe and effective treatment option for patients with HER2 positive and HR positive MBC.
The recent incremental advances made in the treatment of metastatic breast cancer have elicited potential for survival extension in this treatable, yet incurable, population of breast cancer patients. Clinicians have focused on targeted therapies, which aim at signaling receptors such as the human epidermal receptor superfamily, the estrogen receptor, VEGF, the insulin-like growth factor receptor, the hepatocyte growth factor receptor (cMET), phosphoinositide 3-kinase, mTOR, and many others. Clin Cancer Res; 17(17); 5559–61. ©2011 AACR.
Cross-talk between receptor tyrosine kinases and the oestrogen receptor (ER) is implicated in resistance to endocrine therapy. We investigated whether AEE788 (a combined inhibitor of EGFR, HER2 and VEGFR) plus tamoxifen or letrozole enhanced the individual anti-tumour effects of these agents.
Breast cancer cell lines modelling endocrine-resistant and -sensitive disease were engineered to express aromatase (A) and examined using proliferation, western blotting and ER-alpha transcription assays.
AEE788 enhanced the anti-proliferative effect of tamoxifen and letrozole in ER(+) cell lines (MCF-7 2A, ZR75.1 A3 and BT474 A3). This associated with an elevated G1 arrest and nuclear accumulation of p27. It is noteworthy that AEE788 alone or in combination with endocrine therapy increased the expression of progesterone receptor (PGR) and TFF1 in BT474 A3 cells. This may indicate a mechanism of resistance to AEE788 in ER(+)/HER2(+) breast cancers. In a ZR75.1 A3 xenograft, AEE788 alone or in combination with tamoxifen provided no further benefit compared with letrozole. However, letrozole plus AEE788 produced a significantly greater inhibition of tumour growth compared with letrozole alone.
These data suggest that AEE788 plus letrozole in breast cancer overexpressing HER2 may provide superior anti-tumour activity, compared with single agents.
TAnDEM is the first randomized phase III study to combine a hormonal agent and trastuzumab without chemotherapy as treatment for human epidermal growth factor receptor 2 (HER2)/hormone receptor-copositive metastatic breast cancer (MBC).
Postmenopausal women with HER2/hormone receptor-copositive MBC were randomly assigned to anastrozole (1 mg/d orally) with or without trastuzumab (4 mg/kg intravenous infusion on day 1, then 2 mg/kg every week) until progression. The primary end point was progression-free survival (PFS) in the intent-to-treat population. Results Overall, 103 patients received trastuzumab plus anastrozole; 104 received anastrozole alone. Patients in the trastuzumab plus anastrozole arm experienced significant improvements in PFS compared with patients receiving anastrozole alone (hazard ratio = 0.63; 95% CI, 0.47 to 0.84; median PFS, 4.8 v 2.4 months; log-rank P = .0016). In patients with centrally confirmed hormone receptor positivity (n = 150), median PFS was 5.6 and 3.8 months in the trastuzumab plus anastrozole and anastrozole alone arms, respectively (log-rank P = .006). Overall survival in the overall and centrally confirmed hormone receptor-positive populations showed no statistically significant treatment difference; however, 70% of patients in the anastrozole alone arm crossed over to receive trastuzumab after progression on anastrozole alone. Incidence of grade 3 and 4 adverse events was 23% and 5%, respectively, in the trastuzumab plus anastrozole arm, and 15% and 1%, respectively, in the anastrozole alone arm; one patient in the combination arm experienced New York Heart Association class II congestive heart failure.
Trastuzumab plus anastrozole improves outcomes for patients with HER2/hormone receptor-copositive MBC compared with anastrozole alone, although adverse events and serious adverse events were more frequent with the combination.
Cross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment of hormone receptor (HR) -positive metastatic breast cancer (MBC).
Postmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2-positive population. Results In HR-positive, HER2-positive patients (n = 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; P = .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit (responsive or stable disease >or= 6 months) was significantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] = 0.4; 95% CI, 0.2 to 0.8; P = .003). Patients with centrally confirmed HR-positive, HER2-negative tumors (n = 952) had no improvement in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as a significant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR = 0.78; 95% CI, 0.57 to 1.07; P = .117). Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable.
This trial demonstrated that a combined targeted strategy with letrozole and lapatinib significantly enhances PFS and clinical benefit rates in patients with MBC that coexpresses HR and HER2.
To compare the clinical activity of the pure antiestrogen fulvestrant at 500 mg/mo (double the approved dose) with the aromatase inhibitor anastrozole as first-line endocrine therapy for advanced hormone receptor-positive breast cancer in postmenopausal women.
FIRST (Fulvestrant First-Line Study Comparing Endocrine Treatments) is a phase II, randomized, open-label, multicenter study of a fulvestrant high-dose (HD) regimen (500 mg/mo plus 500 mg on day 14 of month 1) versus anastrozole (1 mg/d). The primary efficacy end point was clinical benefit rate (CBR), defined as the proportion of patients experiencing an objective response (OR) or stable disease for > or = 24 weeks. The primary analysis was performed 6 months after the last patient was randomly assigned.
CBR was similar for fulvestrant HD (n = 102) and anastrozole (n = 103), 72.5% v 67.0%, respectively (odds ratio, 1.30; 95% CI, 0.72 to 2.38; P = .386). Objective response rate (ORR) was also similar between treatments: fulvestrant HD, 36.0%; anastrozole, 35.5%. Time to progression (TTP) was significantly longer for fulvestrant versus anastrozole (median TTP not reached for fulvestrant HD v 12.5 months for anastrozole; hazard ratio, 0.63; 95% CI, 0.39 to 1.00; P = .0496). Duration of OR and CB also numerically favored fulvestrant HD. Both treatments were well tolerated, with no significant differences in the incidence of prespecified adverse events.
First-line fulvestrant HD was at least as effective as anastrozole for CBR and ORR and was associated with significantly longer TTP. Fulvestrant HD was generally well tolerated, with a safety profile similar to that of anastrozole.
Cross-talk between the estrogen receptor (ER) and the phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways is a mechanism of resistance to endocrine therapy, and blockade of both pathways enhances antitumor activity in preclinical models. This study explored whether sensitivity to letrozole was enhanced with the oral mTOR inhibitor, everolimus (RAD001).
Two hundred seventy postmenopausal women with operable ER-positive breast cancer were randomly assigned to receive 4 months of neoadjuvant treatment with letrozole (2.5 mg/day) and either everolimus (10 mg/day) or placebo. The primary end point was clinical response by palpation. Mandatory biopsies were obtained at baseline and after 2 weeks of treatment (ie, day 15). Samples were assessed for PI3K mutation status (PIK3CA) and for pharmacodynamic changes of Ki67, phospho-S6, cyclin D1, and progesterone receptor (PgR) by immunohistochemistry.
Response rate by clinical palpation in the everolimus arm was higher than that with letrozole alone (ie, placebo; 68.1% v 59.1%), which was statistically significant at the preplanned, one-sided, alpha = 0.1 level (P = .062). Marked reductions in progesterone receptor and cyclin D1 expression occurred in both treatment arms, and dramatic downregulation of phospho-S6 occurred only in the everolimus arm. An antiproliferative response, as defined by a reduction in Ki67 expression to natural logarithm of percentage positive Ki67 of less than 1 at day 15, occurred in 52 (57%) of 91 patients in the everolimus arm and in 25 (30%) of 82 patients in the placebo arm (P < .01). The safety profile was consistent with historical results of everolimus monotherapy; grades 3 to 4 adverse events occurred in 22.6% of patients who received everolimus and in 3.8% of patients who received placebo.
Everolimus significantly increased letrozole efficacy in neoadjuvant therapy of patients with ER-positive breast cancer.
Unlabelled:
PURPOSE To improve on current standards for breast cancer prognosis and prediction of chemotherapy benefit by developing a risk model that incorporates the gene expression-based "intrinsic" subtypes luminal A, luminal B, HER2-enriched, and basal-like. METHODS A 50-gene subtype predictor was developed using microarray and quantitative reverse transcriptase polymerase chain reaction data from 189 prototype samples. Test sets from 761 patients (no systemic therapy) were evaluated for prognosis, and 133 patients were evaluated for prediction of pathologic complete response (pCR) to a taxane and anthracycline regimen.
Results:
The intrinsic subtypes as discrete entities showed prognostic significance (P = 2.26E-12) and remained significant in multivariable analyses that incorporated standard parameters (estrogen receptor status, histologic grade, tumor size, and node status). A prognostic model for node-negative breast cancer was built using intrinsic subtype and clinical information. The C-index estimate for the combined model (subtype and tumor size) was a significant improvement on either the clinicopathologic model or subtype model alone. The intrinsic subtype model predicted neoadjuvant chemotherapy efficacy with a negative predictive value for pCR of 97%. CONCLUSION Diagnosis by intrinsic subtype adds significant prognostic and predictive information to standard parameters for patients with breast cancer. The prognostic properties of the continuous risk score will be of value for the management of node-negative breast cancers. The subtypes and risk score can also be used to assess the likelihood of efficacy from neoadjuvant chemotherapy.
Human breast tumours are diverse in their natural history and in their responsiveness to treatments. Variation in transcriptional programs accounts for much of the biological diversity of human cells and tumours. In each cell, signal transduction and regulatory systems transduce information from the cell's identity to its environmental status, thereby controlling the level of expression of every gene in the genome. Here we have characterized variation in gene expression patterns in a set of 65 surgical specimens of human breast tumours from 42 different individuals, using complementary DNA microarrays representing 8,102 human genes. These patterns provided a distinctive molecular portrait of each tumour. Twenty of the tumours were sampled twice, before and after a 16-week course of doxorubicin chemotherapy, and two tumours were paired with a lymph node metastasis from the same patient. Gene expression patterns in two tumour samples from the same individual were almost always more similar to each other than either was to any other sample. Sets of co-expressed genes were identified for which variation in messenger RNA levels could be related to specific features of physiological variation. The tumours could be classified into subtypes distinguished by pervasive differences in their gene expression patterns.
The purpose of this study was to classify breast carcinomas based on variations in gene expression patterns derived from cDNA microarrays and to correlate tumor characteristics to clinical outcome. A total of 85 cDNA microarray experiments representing 78 cancers, three fibroadenomas, and four normal breast tissues were analyzed by hierarchical clustering. As reported previously, the cancers could be classified into a basal epithelial-like group, an ERBB2-overexpressing group and a normal breast-like group based on variations in gene expression. A novel finding was that the previously characterized luminal epithelial/estrogen receptor-positive group could be divided into at least two subgroups, each with a distinctive expression profile. These subtypes proved to be reasonably robust by clustering using two different gene sets: first, a set of 456 cDNA clones previously selected to reflect intrinsic properties of the tumors and, second, a gene set that highly correlated with patient outcome. Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospective study showed significantly different outcomes for the patients belonging to the various groups, including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups.
Data suggest that breast cancer growth is regulated by coordinated actions of the estrogen receptor (ER) and various growth factor receptor signaling pathways. In tumors with active growth factor receptor signaling (e.g., HER2 amplification), tamoxifen may lose its estrogen antagonist activity and may acquire more agonist-like activity, resulting in tumor growth stimulation. Because treatments designed to deprive the ER of its ligand estrogen will reduce signaling from both nuclear and membrane ER, aromatase inhibitors might be expected to be superior to tamoxifen in tumors with high growth factor receptor content, such as those overexpressing HER2. Recent clinical studies suggest that this is the case in humans, as trials of aromatase inhibitors show superior results compared with tamoxifen, especially in tumors overexpressing HER2. Although estrogen deprivation therapy is often effective in ER-positive breast cancer, de novo and acquired resistance are still problematic. Experimental models suggest that in one form of resistance to estrogen deprivation therapy, the tumor becomes supersensitive to low residual estrogen concentrations perhaps because of activation of mitogen-activated protein kinase. Such tumors respond to additional treatment with fulvestrant or even tamoxifen. On the other hand, in tumors overexpressing HER2, acquired resistance to estrogen deprivation therapy involves the loss of ER and ER-regulated genes and further up-regulation of growth factor signaling rendering the tumor hormonal therapy resistant. This process can be delayed or reversed by simultaneous treatment with growth factor pathway inhibitors. This strategy is now being tested in clinical trials.
Purpose: Experimental data suggest a complex cross-talk between HER-2 and estrogen receptor, and it has been hypothesized that HER-2-positive tumors may be less responsive to certain endocrine treatments. Clinical data, however, have been conflicting. We have conducted a meta-analysis on the interaction between the response to endocrine treatment and the overexpression of HER-2 in metastatic breast cancer.
Experimental Design: Studies have been identified by searching the Medline, Embase, and American Society of Clinical Oncology abstract databases. Selection criteria were (a) metastatic breast cancer, (b) endocrine therapy (any line of treatment), and (c) evaluation of HER-2 expression (any method). For each study, the relative risk for treatment failure for HER-2-positive over HER-2-negative patients with 95% confidence interval was calculated as an estimate of the predictive effect of HER-2. Pooled estimates of the relative risk were computed by the Mantel-Haenszel method.
Results: Twelve studies (n = 2,379 patients) were included in the meta-analysis. The overall relative risk was 1.42 (95% confidence interval, 1.32-1.52; P < 0.00001; test for heterogeneity = 0.380). For studies involving tamoxifen, the pooled relative risk was 1.33 (95% confidence interval, 1.20-1.48; P < 0.00001; test for heterogeneity = 0.97); for studies involving other hormonal drugs, a pooled relative risk of 1.49 (95% confidence interval, 1.36-1.64; P < 0.00001; test for heterogeneity = 0.08) was estimated. A second meta-analysis limited to tumors that were either estrogen receptor positive, estrogen receptor unknown, or estrogen receptor negative/progesterone receptor positive yielded comparable results.
Conclusions: HER-2-positive metastatic breast cancer is less responsive to any type of endocrine treatment. This effect holds in the subgroup of patients with positive or unknown steroid receptors.
Arimidex, tamoxifen alone, or in combination (ATAC) trial of anastrozole (Arimidex) versus tamoxifen or a combination of the two in 9,366 postmenopausal patients with primary breast cancer found a significant improvement in disease-free survival and time to recurrence (TTR) for anastrozole compared with tamoxifen, that was restricted to patients with hormone receptor-positive (ie, estrogen receptor-positive [ER+] and/or progesterone receptor-positive [PgR+]) disease, the target population for these therapies. We retrospectively tested the hypothesis that this benefit might differ according to PgR status.
TTR was compared between the three treatment groups for subgroups defined by ER and PgR status using Cox's proportional hazards model, with and without adjustment for baseline variables.
The unadjusted hazard ratio (HR) for anastrozole versus tamoxifen for TTR was 0.74 (95% CI, 0.64 to 0.87) for women with either ER+ or PgR+ tumors. In the ER+/PgR+ subgroup (n = 3,834) the HR was 0.84 (95% CI, 0.69 to 1.02) compared with 0.43 (95% CI, 0.31 to 0.61) in the ER+/PgR-negative (PgR-) subgroup (n = 880). In the adjusted model the HRs were 0.83 and 0.45, respectively.
Time to recurrence was longer for anastrozole- than tamoxifen-treated patients in both ER+/PgR+ and ER+/PgR- subgroups, but the benefit was substantially greater in the PgR- subgroup. As this was an "exploratory" analysis, this effect should be considered as hypothesis generating and assessed prospectively in other trials comparing the adjuvant use of an aromatase inhibitor with tamoxifen.
Enhancing the benefit of endocrine therapy by overcoming de novo or acquired resistance remains an important goal in systemic breast cancer therapy. Progress continues to be made in elucidating the molecular pathways by which estrogen receptor–positive breast cancer cells escape from endocrine therapy. The increasing recognition of the roles of epidermal growth factor receptor (EGFR) and human EGFR2 in cross-talk activation of estrogen receptor signaling has led to studies aimed at identifying whether small-molecule tyrosine kinase inhibitors targeted against these receptors give additive or synergistic effects when combined with endocrine agents. Activation of the phosphatidylinositol-3-OH kinase/Akt pathway has also been associated with resistance to either tamoxifen or estrogen deprivation, and preclinical studies have shown that the mammalian target of rapamycin antagonist temsirolimus can restore endocrine sensitivity in breast cancer cells. Randomized phase II trials of aromatase inhibitors combined with EGFR/human EGFR2 tyrosine kinase inhibitors or mammalian target of rapamycin antagonists have been completed in both the neoadjuvant and advanced breast cancer settings. Larger phase III trials with both approaches are now in progress and have been powered to detect whether either strategy can significantly prolong time to disease progression compared with endocrine therapy alone. The correlation of molecular and clinical results from these ongoing studies will be important to establish appropriate biological variables for selecting those patients who may benefit most from this combined approach.
Estrogen receptor (ER) and/or progesterone receptor expression occurs in approximately 50% HER2 positive (HER2+) breast cancers and cross-talk between the estrogen and HER2 pathways promotes endocrine therapy resistance. The efficacy of the aromatase inhibitor letrozole in combination with trastuzumab was therefore tested in a Phase 2 study.
Patients with ER+ and/or PgR+ and HER2+ (IHC 2+ or 3+ or FISH+) advanced breast cancer were treated with trastuzumab plus letrozole until disease progression or unacceptable toxicity.
Thirty-three patients were enrolled, of which thirty one were considered evaluable. The majority of patients (82%) had received tamoxifen and 82% had HER2 FISH+ and/or IHC 3+ tumors. Eight patients responded (1 CR and 7 PR) for an overall response rate (ORR) of 26% and a clinical benefit rate (CBR) of 52%. The median time to progression (TTP) was 5.8 months and the median duration of response (DOR) was 20.6+ months. Excluding IHC 2+, FISH- tumors, the OR was 24%, CBR 44%, TTP 5.5 months and DOR 17+ months. The combination was well tolerated with only two toxicity events requiring termination of study medication.
Combined trastuzumab and letrozole treatment for patients with HER2+ and ER+ advanced breast cancer produced durable responses consistently lasting at least 1 year in one quarter of the patients. While these data are promising for a subgroup, for half the patients, trastuzumab plus letrozole was inactive. This finding demonstrates ER+ HER2+ advanced disease is heterogeneous and additional agents will be required for optimal management based on targeted therapeutics alone.
To determine the relationship between quantitative estrogen-receptor (ER) and progesterone-receptor (PgR) expression and human epidermal growth factor 2 (HER-2) status with time to recurrence (TTR) in postmenopausal women with hormone receptor-positive primary breast cancer treated with anastrozole or tamoxifen as adjuvant therapy.
Formalin-fixed, paraffin-embedded tumor blocks were retrospectively collected from patients in the monotherapy arms of the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial and centrally tested for ER, PgR and HER-2. ER and PgR were scored using continuous scales and HER-2 was scored as 0 to 3+ with 2+ cases being analyzed by fluorescence in situ hybridization.
Blocks were collected from 2,006 of 5,880 eligible patients. Tissue was assessable and ER and/or PgR positivity confirmed centrally in 1,782 cases. In these, TTR was longer for anastrozole than for tamoxifen by a similar extent to that in the overall trial. None of the three biomarkers identified a set of patients with differential benefit from anastrozole over tamoxifen. Patients with low ER, low PgR, and high HER-2 expression had a poorer prognosis with either drug. Only 2.6% of patients in the highest quartile of PgR experienced recurrence after 5 years, compared with 13.2% in the lowest quartile.
Quantitative expression of ER and PgR and HER-2 status did not identify patients with differential relative benefit from anastrozole over tamoxifen: TTR was longer for anastrozole than for tamoxifen in all molecular subgroups. Low ER or PgR or high HER-2 expression are associated with a high risk of recurrence with either anastrozole or tamoxifen.
Not all breast cancers respond to tamoxifen, and many develop resistance despite initial benefit. We used an in vivo model of estrogen receptor (ER)-positive breast cancer (MCF-7 xenografts) to investigate mechanisms of this resistance and develop strategies to circumvent it. Epidermal growth factor receptor (EGFR) and HER2, which were barely detected in control estrogen-treated tumors, increased slightly with tamoxifen and were markedly increased when tumors became resistant. Gefitinib, which inhibits EGFR/HER2, improved the antitumor effect of tamoxifen and delayed acquired resistance, but had no effect on estrogen-stimulated growth. Phosphorylated levels of p42/44 and p38 mitogen-activated protein kinases (both downstream of EGFR/HER2) were increased in the tamoxifen-resistant tumors and were suppressed by gefitinib. There was no apparent increase in phosphorylated AKT (also downstream of EGFR/HER2) in resistant tumors, but it was nonetheless suppressed by gefitinib. Phosphorylated insulin-like growth factor-IR (IGF-IR), which can interact with both EGFR and membrane ER, was elevated in the tamoxifen-resistant tumors compared with the sensitive group. However, ER-regulated gene products, including total IGF-IR itself and progesterone receptor, remained suppressed even at the time of acquired resistance. Tamoxifen's antagonism of classic ER genomic function was retained in these resistant tumors and even in tumors that overexpress HER2 (MCF-7 HER2/18) and are de novo tamoxifen-resistant. In conclusion, EGFR/HER2 may mediate tamoxifen resistance in ER-positive breast cancer despite continued suppression of ER genomic function by tamoxifen. IGF-IR expression remains dependent on ER but is activated in the tamoxifen-resistant tumors. This study provides a rationale to combine HER inhibitors with tamoxifen in clinical studies, even in tumors that do not initially overexpress EGFR/HER2.
Purpose.—To develop a guideline to improve the accuracy of immunohistochemical (IHC) estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer and the utility of these receptors as predictive markers.
Methods.—The American Society of Clinical Oncology and the College of American Pathologists convened an international Expert Panel that conducted a systematic review and evaluation of the literature in partnership with Cancer Care Ontario and developed recommendations for optimal IHC ER/PgR testing performance.
Results.—Up to 20% of current IHC determinations of ER and PgR testing worldwide may be inaccurate (false negative or false positive). Most of the issues with testing have occurred because of variation in pre-analytic variables, thresholds for positivity, and interpretation criteria.
Recommendations.—The Panel recommends that ER and PgR status be determined on all invasive breast cancers and breast cancer recurrences. A testing algorithm that relies on accurate, reproducible assay performance is proposed. Elements to reliably reduce assay variation are specified. It is recommended that ER and PgR assays be considered positive if there are at least 1% positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal (normal epithelial elements) and external controls. The absence of benefit from endocrine therapy for women with ER-negative invasive breast cancers has been confirmed in large overviews of randomized clinical trials.
Purpose
To update the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer.
Methods
ASCO/CAP convened an Update Committee that included coauthors of the 2007 guideline to conduct a systematic literature review and update recommendations for optimal HER2 testing.
Results
The Update Committee identified criteria and areas requiring clarification to improve the accuracy of HER2 testing by immunohistochemistry (IHC) or in situ hybridization (ISH). The guideline was reviewed and approved by both organizations.
Recommendations
The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive (early stage or recurrence) breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive). Testing criteria define HER2-positive status when (on observing within an area of tumor that amounts to > 10% of contiguous and homogeneous tumor cells) there is evidence of protein overexpression (IHC) or gene amplification (HER2 copy number or HER2/CEP17 ratio by ISH based on counting at least 20 cells within the area). If results are equivocal (revised criteria), reflex testing should be performed using an alternative assay (IHC or ISH). Repeat testing should be considered if results seem discordant with other histopathologic findings. Laboratories should demonstrate high concordance with a validated HER2 test on a sufficiently large and representative set of specimens. Testing must be performed in a laboratory accredited by CAP or another accrediting entity. The Update Committee urges providers and health systems to cooperate to ensure the highest quality testing. This guideline was developed through a collaboration between the American Society of Clinical Oncology and the College of American Pathologists and has been published jointly by invitation and consent in both Journal of Clinical Oncology and the Archives of Pathology & Laboratory Medicine. Copyright © 2013 American Society of Clinical Oncology and College of American Pathologists. All rights reserved. No part of this document may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without written permission by American Society of Clinical Oncology or College of American Pathologists.
Breast cancer is one of the most prevalent and devastating malignant diseases in women worldwide. Fortunately, while breast cancer incidence is still increasing, its death rate is declining. This is mainly due to early diagnosis and potent therapies such as blockade of estrogen receptor- or of ErbB2 (HER2-neu) membrane receptorsignaling. In recent years, the PI3K/AKT/mTOR pathway, which transmits signals from the cell membrane into the nucleus and activates multiple oncogenic programs, has been found to play a crucial role in the regulation of breast cancer cell growth. This pathway is densely interconnected with a multitude of other important regulatory systems for glucose-, lipid- and amino acid-metabolism, for energy balance, and for autophagy. It has been found that PI3K/AKT/mTOR signaling modulates estrogen receptor function. Using transverse and feedback regulatory loops the PI3K/AKT/mTOR cascade can communicate with concurrent and with upstream systems. Thus, PI3K/AKT/mTOR is a crucial element within a complicated signaling network. This pathway is hyperactive in more than 70% of breast tumors. Hence, the protein kinases located along this route represent very attractive and promising drug targets for breast cancer therapy. Currently, numerous small molecular drugs that inhibit PI3K, AKT and/or mTOR are being developed in preclinical and clinical models of breast cancer. Some of these compounds are highly selective blocking only one particular kinase complex, whereas others interfere with two (mTORC1+mTORC2) or even three effectors (PI3K+mTORC1+mTORC2) of the pathway. Due to the many interactions with other regulatory systems, silencing of the pathway can cause unexpected results. Therefore, detailed preclinical and clinical evaluation of these compounds as single drugs and in combination is required to achieve optimal results with maximal clinical benefit and acceptable toxicity. Also, reliable biomarkers for the identification of patient subsets that will maximally benefit from PI3K/AKT/mTOR inhibition need to be developed. Thus, selective silencing of PI3K/AKT/mTOR signaling represents a promising approach for breast cancer and might prove useful when combined with other drugs. Here we review the current preclinical and clinical data and compare the potential benefits of multi- versus single-targeting PI3K/AKT/mTOR drugs.
mTOR inhibition reverses trastuzumab resistance via the hyperactivated PIK/AKT/mTOR pathway due to PTEN loss, by sensitising PTEN-deficient tumours to trastuzumab. The BOLERO-1 study assessed the efficacy and safety of adding everolimus to trastuzumab and paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer.
In this phase 3, randomised, double-blind trial, patients were enrolled across 141 sites in 28 countries. Eligible patients were aged 18 years or older, with locally assessed HER2-positive advanced breast cancer, with Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, who had not received previous trastuzumab or chemotherapy for advanced breast cancer within 12 months of randomisation, had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) or bone lesions in the absence of measurable disease, without previous systemic treatment for advanced disease except endocrine therapy. Patients were randomly assigned (2:1) with an interactive voice and web response system to receive either 10 mg everolimus once a day orally or placebo plus weekly trastuzumab intravenously at 4 mg/kg loading dose on day 1 with subsequent weekly doses of 2 mg/kg of each 4 week cycle plus paclitaxel intravenously at a dose of 80 mg/m(2) on days 1, 8, and 15 of each 4 week cycle. Randomisation was stratified according to previous use of trastuzumab and visceral metastasis. Patients and investigators were masked to the assigned treatments. Identity of experimental treatments was concealed by use of everolimus and placebo that were identical in packaging, labelling, appearance, and administration schedule. The two primary objectives were investigator-assessed progression-free survival in the full study population and in the subset of patients with hormone receptor-negative breast cancer at baseline; the latter was added during the course of the study, before unmasking based on new clinical and biological findings from other studies. All efficacy analyses were based on the intention-to-treat population. Enrolment for this trial is closed and results of the final progression-free survival analyses are presented here. This trial is registered with ClinicalTrials.gov, number NCT00876395.
Between Sept 10, 2009, and Dec 16, 2012, 719 patients were randomly assigned to receive everolimus (n=480) or placebo (n=239). Median follow-up was 41·3 months (IQR 35·4-46·6). In the full population, median progression-free survival was 14·95 months (95% CI 14·55-17·91) with everolimus versus 14·49 months (12·29-17·08) with placebo (hazard ratio 0·89, 95% CI 0·73-1·08; p=0·1166). In the HR-negative subpopulation (n=311), median progression-free survival with everolimus was 20·27 months (95% CI 14·95-24·08) versus 13·08 months (10·05-16·56) with placebo (hazard ratio 0·66, 95% CI 0·48-0·91; p=0·0049); however, the protocol-specified significance threshold (p=0·0044) was not crossed. The most common adverse events with everolimus were stomatitis (314 [67%] of 472 patients in the everolimus group vs 77 [32%] of 238 patients in the placebo group), diarrhoea (267 [57%] vs 111 [47%] patients), and alopecia (221 [47%] vs 125 [53%]). The most frequently reported grade 3 or 4 adverse events in the everolimus group versus the placebo group were neutropenia (117 [25%] vs 35 [15%]), stomatitis (59 [13%] vs three [1%]), anaemia (46 [10%] vs six [3%]) and diarrhoea (43 [9%] vs 10 [4%]) On-treatment adverse event-related deaths were reported in 17 (4%) patients in the everolimus group and none in the placebo group.
Although progression-free survival was not significantly different between groups in the full analysis population, the 7·2 months prolongation we noted with the addition of everolimus in the HR-negative, HER2-positive population warrants further investigation, even if it did not meet prespecified criteria for significance. The safety profile was generally consistent with what was previously reported in BOLERO-3. Proactive monitoring and early management of adverse events in patients given everolimus and chemotherapy is crucial.
Novartis Pharmaceuticals.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Learning Objectives
After completing this course, the reader will be able to:
Explain how surgery in combination with systemic therapy may offer significantly improved survival outcomes in selected patients with metastatic breast cancer. Appreciate the value of chest x-rays in follow-up to identify patients with pulmonary or sternal metastases who may be candidates for surgical resection. Recognize that the concept of a “cure” in breast cancer is evolving to mean a prolonged period of survival without significant symptoms.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
Although metastatic breast cancer is widely believed to carry a grim prognosis, treatment developments over the past 25 years have greatly improved survival outcomes in these patients. In selected cases, aggressive treatment approaches may occasionally result in long-term survival of 15 years or more. This review considers the role of surgery in the treatment of single or multiple metastatic lesions restricted to one site. For each site, available literature from 1992–2002 was assessed to determine the role of surgery on survival outcomes and to determine appropriate criteria for selecting the best candidates for surgery. For lung, liver, brain, and sternum metastases, the use of surgery with or without adjuvant therapy resulted in greater median survival times and 5-year survival rates. The best candidate for surgery had no evidence of additional metastatic disease, good performance status, and a long disease-free interval after treatment of the primary tumor. Current treatment standards for breast cancer follow-up do not include imaging studies other than mammography. The addition of chest x-rays as part of routine follow-up should be considered as a cost-effective approach for early assessment of metastases to the lung or sternum that may be appropriate for surgical excision.
Disease progression in patients with HER2-positive breast cancer receiving trastuzumab might be associated with activation of the PI3K/Akt/mTOR intracellular signalling pathway. We aimed to assess whether the addition of the mTOR inhibitor everolimus to trastuzumab might restore sensitivity to trastuzumab.
In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited women with HER2-positive, trastuzumab-resistant, advanced breast carcinoma who had previously received taxane therapy. Eligible patients were randomly assigned (1:1) using a central patient screening and randomisation system to daily everolimus (5 mg/day) plus weekly trastuzumab (2 mg/kg) and vinorelbine (25 mg/m(2)) or to placebo plus trastuzumab plus vinorelbine, in 3-week cycles, stratified by previous lapatinib use. The primary endpoint was progression-free survival (PFS) by local assessment in the intention-to-treat population. We report the final analysis for PFS; overall survival follow-up is still in progress. This trial is registered with ClinicalTrials.gov, number NCT01007942.
Between Oct 26, 2009, and May 23, 2012, 569 patients were randomly assigned to everolimus (n=284) or placebo (n=285). Median follow-up at the time of analysis was 20·2 months (IQR 15·0-27·1). Median PFS was 7·00 months (95% CI 6·74-8·18) with everolimus and 5·78 months (5·49-6·90) with placebo (hazard ratio 0·78 [95% CI 0·65-0·95]; p=0·0067). The most common grade 3-4 adverse events were neutropenia (204 [73%] of 280 patients in the everolimus group vs 175 [62%] of 282 patients in the placebo group), leucopenia (106 [38%] vs 82 [29%]), anaemia (53 [19%] vs 17 [6%]), febrile neutropenia (44 [16%] vs ten [4%]), stomatitis (37 [13%] vs four [1%]), and fatigue (34 [12%] vs 11 [4%]). Serious adverse events were reported in 117 (42%) patients in the everolimus group and 55 (20%) in the placebo group; two on-treatment deaths due to adverse events occurred in each group.
The addition of everolimus to trastuzumab plus vinorelbine significantly prolongs PFS in patients with trastuzumab-resistant and taxane-pretreated, HER2-positive, advanced breast cancer. The clinical benefit should be considered in the context of the adverse event profile in this population.
Novartis Pharmaceuticals Corporation.
Background:
Identification and validation of biomarkers is increasingly important for the integration of novel targeted agents in the treatment of cancer. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway represents a promising therapeutic target in breast carcinoma, and inhibitors targeting different nodes of the PI3K/Akt/mTOR axis are in development. Identification of biomarkers to help select patients who are most likely to benefit from these treatments is an essential unmet need.
Design:
MEDLINE and international conference abstracts were searched for evidence of markers of sensitivity to PI3K/Akt/mTOR pathway inhibitors in breast cancer patients and preclinical models.
Results:
Preclinical evidence suggests that PI3K/Akt/mTOR pathway aberrations, notably in PIK3CA, may identify a subpopulation of patients with breast cancer who preferentially respond to PI3K/Akt/mTOR inhibitors. However, additional markers are needed to identify all patients with de novo sensitivity to PI3K/Akt/mTOR pathway inhibition. Early clinical studies to validate these biomarkers have as yet been inconclusive.
Conclusions:
Prospective, adequately designed and powered clinical trials are needed to test candidate biomarkers of sensitivity to PI3K/Akt/mTOR pathway inhibitors in patients with breast cancer, and to determine whether certain PI3K/Akt/mTOR pathway inhibitors are more appropriate in different subtypes depending on the pattern of molecular alteration.
Despite the fact that most breast cancer patients have estrogen receptor (ER) α-positive tumors, up to 50% of the patients are or soon develop resistance to endocrine therapy. It is recognized that HER2 activation is one of the major mechanisms contributing to endocrine resistance. In this study, we report that the ER coactivator MED1 is a novel cross-talk point for the HER2 and ERα pathways. Tissue microarray analysis of human breast cancers revealed that MED1 expression positively correlates most strongly with HER2 status of the tumors. MED1 was highly phosphorylated, in a HER2-dependent manner, at the site known to be critical for its activation. Importantly, RNAi-mediated attenuation of MED1 sensitized HER2-overexpressing cells to tamoxifen treatment. MED1 and its phosphorylated form, but not the corepressors N-CoR and SMRT, were recruited to the ERα target gene promoter by tamoxifen in HER2-overexpressing cells. Significantly, MED1 attenuation or mutation of MED1 phosphorylation sites was sufficient to restore the promoter recruitment of N-CoR and SMRT. Notably, we found that MED1 is required for the expression of not only traditional E2-ERα target genes but also the newly described EGF-ERα target genes. Our results additionally indicated that MED1 is recruited to the HER2 gene and required for its expression. Taken together, these findings support a key role for MED1 in HER2-mediated tamoxifen resistance and suggest its potential usage as a therapeutic target to simultaneously block both ERα and HER2 pathways for the treatment of this type of endocrine resistant breast cancer. Cancer Res; 72(21); 1-10. ©2012 AACR.
Systemic chemotherapy is the mainstay of treatment for metastatic breast cancer with the role of surgery being strictly limited for palliation of metastatic complications or locoregional relapse. An increasing number of studies examining the role of therapeutic hepatic metastasectomy show encouraging survival results. A systematic review was undertaken to define its safety, efficacy and to identify prognostic factors associated with survival.
Electronic search of the MEDLINE and PubMed databases (January 2000-January 2011) to identify studies reporting outcomes of hepatectomy for breast cancer liver metastases (BCLM) with hepatectomy was undertaken. Two reviewers independently appraised each study using a predetermined protocol. Safety and clinical efficacy was synthesised through a narrative review with full tabulation of results of all included studies.
Nineteen studies were examined. This comprised of 553 patients. Hepatectomy for BCLM was performed at a rate of 1.8 (range, 0.7-7.7) cases per year in reported series. The median time to liver metastases occurred at a median of 40 (range, 23-77) months. The median mortality and complication rate were 0% (range, 0-6%) and 21% (range, 0-44%), respectively. The median overall survival was 40 (range, 15-74) months and median 5-year survival rate was 40% (range, 21-80%). Potential prognostic factors associated with a poorer overall survival include a positive liver surgical margin and hormone refractory disease.
Hepatectomy is rarely performed for BCLM but the studies described in this review indicate consistent results with superior 5-year survival for selected patients with isolated liver metastases and in those with well controlled minimal extrahepatic disease. To evaluate its efficacy and control for selection bias, a randomised trial of standard chemotherapy with or without hepatectomy for BCLM is warranted.
Liver resection (LR) within a multimodal treatment concept of hepatic metastases (HM) that results from breast cancer has been controversially discussed. The aim of this study was to evaluate the outcome of LR in patients with hepatic breast cancer metastases.
Prospectively collected data from 41 consecutive patients who underwent LR for HM between 1999 and 2008 were analyzed retrospectively. Univariate and multivariate analyses were performed to assess potential prognostic factors.
Segmental resection was performed in 46% and major hepatectomy in 54% of patients. The postoperative mortality rate was 0%. At a median follow-up of 34 months, 26 patients were alive. The median and 5-year overall survival rates after LR were 58 months and 48%, respectively. The median and 5-year disease-free survivals were 34 months and 31%, respectively. The intrahepatic recurrence-free 5-year survival was 62%. The median survival from time of diagnosis of HM was 79 months. The positive resection margin as well as a disease-free interval between the treatment of the primary tumor and the diagnosis of HM < 1 year were independent predictors of overall survival.
LR of hepatic breast cancer metastases within a multimodal treatment concept is a safe procedure in well-selected patients. Both a short time interval to the development of HM and positive resection margins after LR are strongly associated with worse long-term survival.
The goals of treating patients with metastatic breast cancer are to prolong survival, slow or halt disease progression, and enhance the patient's quality of life. In patients with estrogen receptor (ER)-positive cancers that are not progressing rapidly, endocrine therapy is generally the first treatment option. If a patient initially responds to an endocrine agent and then progresses, another endocrine agent may still provide benefit. Tamoxifen has been used as first-line therapy for metastatic breast cancer for many years. Until recently, no other endocrine agent has shown superiority to tamoxifen in this setting. The nonsteroidal aromatase inhibitors, anastrozole and letrozole, have been widely accepted as second-line therapy after failure of tamoxifen; they have replaced megestrol acetate in this setting. Recently, anastrozole was shown to have at least equivalent efficacy and a superior side effect profile compared with tamoxifen for treating postmenopausal women in the first-line setting. Thus, this aromatase inhibitor has become a viable option for first-line therapy in postmenopausal women. Trials of letrozole in this setting are nearing completion. Exemestane has been shown to be an effective second-line agent and to have at least some efficacy as a third-line agent even after failure of a nonsteroidal aromatase inhibitor. Results are anxiously awaited from trials of new endocrine agents including the first member of a new class of endocrine agent, the estrogen-receptor downregulator class. Semin Oncol 28:291-304.
Expression of ErbB-1 and ErbB-2 (epidermal growth factor receptor and HER2/neu) in breast cancer may cause tamoxifen resistance, but not all studies concur. Additionally, the relationship between ErbB-1 and ErbB-2 expression and response to selective aromatase inhibitors is unknown. A neoadjuvant study for primary breast cancer that randomized treatment between letrozole and tamoxifen provided a context within which these issues could be addressed prospectively.
Postmenopausal patients with estrogen- and/or progesterone receptor-positive (ER+ and/or PgR+) primary breast cancer ineligible for breast-conserving surgery were randomly assigned to 4 months of neoadjuvant letrozole 2.5 mg daily or tamoxifen 20 mg daily in a double-blinded study. Immunohistochemistry (IHC) for ER and PgR was conducted on pretreatment biopsies and assessed by the Allred score. ErbB-1 and ErbB-2 IHC were assessed by intensity and completeness of membranous staining according to published criteria.
For study biopsy-confirmed ER+ and/or PgR+ cases that received letrozole, 60% responded and 48% underwent successful breast-conserving surgery. The response to tamoxifen was inferior (41%, P =.004), and fewer patients underwent breast conservation (36%, P =.036). Differences in response rates between letrozole and tamoxifen were most marked for tumors that were positive for ErbB-1 and/or ErbB-2 and ER (88% v 21%, P =.0004).
ER+, ErbB-1+, and/or ErbB-2+ primary breast cancer responded well to letrozole, but responses to tamoxifen were infrequent. This suggests that ErbB-1 and ErbB-2 signaling through ER is ligand-dependent and that the growth-promoting effects of these receptor tyrosine kinases on ER+ breast cancer can be inhibited by potent estrogen deprivation therapy.
To determine the effect of elevation of serum HER-2/neu on response to hormone therapy.
Seven hundred nineteen metastatic patients with estrogen receptor-positive (ER(+)), progesterone receptor-positive, or both or ER status unknown breast cancer were randomized in three independent clinical trials to receive second-line hormone therapy with either megestrol acetate or an aromatase inhibitor (fadrozole or letrozole). An automated enzyme-linked immunosorbent assay specific for the extracellular domain of the HER-2/neu (c-erbB-2) oncoprotein product was used to detect serum levels.
Two hundred nineteen patients (30%) had elevated serum HER-2/neu protein levels, using the mean + 2 SD (15 ng/mL) from the serum of healthy women as an upper limit. Response to treatment was available for 711 patients. The response rate (complete responses plus partial responses plus stable disease) to endocrine therapy was 45% in 494 patients with non-elevated and 23% in 217 patients with elevated serum HER-2/neu levels (P <.0001). Median duration of treatment response (using the time to progression [TTP] variable for patients who responded) was shorter in the group with elevated serum HER-2/neu levels (11.7 months) compared with the patient group with non-elevated levels (17.4 months). TTP, time to treatment failure, and median survival (17.2 months v 29.6 months) were also significantly shorter in the patients with elevated serum HER-2/neu levels (P <.0001).
Patients with ER(+) and serum HER-2/neu-positive metastatic breast cancer are less likely to respond to hormone treatment and have a shorter duration of response than ER(+) and serum HER-2/neu-negative patients. Their survival duration is also shorter.
Endocrine therapy is the preferred first-line therapy in patients with nonaggressive, receptor-positive, metastatic breast cancer. Endocrine therapies in these patients are as effective as chemotherapy in terms of survival and tumor response. In addition, hormonal therapies produce fewer and less severe adverse effects than does chemotherapy. Classes of endocrine therapy currently on the market include selective estrogen receptor modulators (SERMs), aromatase inhibitors, and progestins. For several decades, tamoxifen has been considered the gold standard of therapy. However, despite its proven efficacy, a high proportion of patients do not respond. Therefore, a need exists for alternative therapies or for agents to use following tamoxifen failure.
This review article highlights the various endocrine options available for patients with advanced breast cancer and discusses new agents on the horizon.
Although more studies are needed to determine the optimal sequence of hormonal therapy and the ideal agent within each class, the availability of new and multiple options is encouraging for women with advanced breast cancer.
Although metastatic breast cancer is widely believed to carry a grim prognosis, treatment developments over the past 25 years have greatly improved survival outcomes in these patients. In selected cases, aggressive treatment approaches may occasionally result in long-term survival of 15 years or more. This review considers the role of surgery in the treatment of single or multiple metastatic lesions restricted to one site. For each site, available literature from 1992-2002 was assessed to determine the role of surgery on survival outcomes and to determine appropriate criteria for selecting the best candidates for surgery. For lung, liver, brain, and sternum metastases, the use of surgery with or without adjuvant therapy resulted in greater median survival times and 5-year survival rates. The best candidate for surgery had no evidence of additional metastatic disease, good performance status, and a long disease-free interval after treatment of the primary tumor. Current treatment standards for breast cancer follow-up do not include imaging studies other than mammography. The addition of chest x-rays as part of routine follow-up should be considered as a cost-effective approach for early assessment of metastases to the lung or sternum that may be appropriate for surgical excision.
Hormonal therapy and the humanised anti-HER2 monoclonal antibody trastuzumab (Herceptin) represent one of the oldest and one of the newest treatment modalities for breast cancer, respectively. Recent data have suggested that HER2 overexpression is associated with resistance to hormonal therapy and there is considerable preclinical evidence to support the existence of interaction or 'cross talk' between HER2 and estrogen-receptor (ER) signalling pathways in breast cancer. Preclinical data also demonstrate that adding trastuzumab to hormonal therapy results in greater antitumour activity than either agent alone. The existence of an inverse relationship between ER expression and HER2 overexpression has also been well established clinically. Thus, a range of clinical trials are now ongoing to determine whether the addition of trastuzumab to hormonal therapy will provide breast cancer patients with benefits in clinical practice. This review describes the rationale for these trials and discusses the potential of therapeutic regimens combining trastuzumab with hormonal therapy.
Learning Objectives
After completing this course, the reader will be able to:
Discuss patterns of resistance to endocrine therapy for breast cancer. Relate differences in resistance patterns in early and advanced disease settings. Identify potential treatment strategies to overcome resistance and/or restore endocrine therapy efficacy.
Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com
Endocrine therapy is the most effective systemic treatment for patients with hormone-receptor-positive (HR+) breast cancer. Unfortunately, efficacy is often limited by the onset of resistance, which is almost inevitable for patients with advanced disease. Several patterns of endocrine resistance are recognizable clinically, including: A) tumors that are inherently insensitive to all attempts at estrogen receptor (ER) targeting despite expression of ER (pan-endocrine therapy resistance); B) tumors that are estrogen dependent but resistant to one or more specific endocrine therapies (agent-selective resistance); and C) tumors that initially respond but subsequently progress (acquired resistance). Current insights into the molecular basis for these resistance patterns are rudimentary, but are most clearly illuminated by investigations that focus on the crosstalk between the ErbB or HER peptide growth factor family and the ER. The data are sufficiently compelling to be addressed by ongoing clinical trials that examine combinations of endocrine agents and either trastuzumab (Herceptin®; Genentech, Inc.; South San Francisco, CA) or ErbB-specific tyrosine kinase (TK) inhibitors. Preliminary data from a small “proof of concept” phase II study of letrozole (Femara®; Novartis Pharmaceuticals Corporation; East Hanover, NJ) and trastuzumab demonstrated durable responses despite tamoxifen (Nolvadex®; AstraZeneca Pharmaceuticals; Wilmington, DE) resistance. Efficacy was variable, however, despite the selection of patients on the basis of ER and ErbB-2 coexpression. Complicating matters further, resistance often occurs in the absence of any evidence for ErbB TK family member expression. In the absence of a clear target, common downstream signal transduction proteins that are known to intersect with the ER pathway can be inhibited to address resistance, including G proteins with farnesyltransferase inhibitors and molecular target of rapamycin (mTOR) with rapamycin analogues. With a number of phase III clinical trials now under way, major advances in the endocrine treatment of advanced disease are possible.
Hepatic metastases from breast cancer signal a dismal prognosis, with a median survival of 9.5 months.
Twenty breast cancer patients with liver metastases underwent hepatic resection, biopsy, or ablation between 1995 and 2004. Hormone receptor status and Her-2/neu expression of primary and metastatic tumors were correlated with overall survival.
At a mean follow-up of 39 months after hepatic resection, median survival was 32 months. Patients undergoing anatomic resection with or without ablation lived significantly longer than those undergoing more limited resections (46 vs. 25 months, P = .016). Survival was significantly greater in patients with estrogen receptor (ER)-positive primary (P = .02) and metastatic (P < .004) tumors, Her-2/neu-positive metastases (P = .02), </=2 hepatic metastases (P < .002), and age >50 years at metastasectomy (P = .02).
The ER status of the primary tumor and ER and Her-2/neu status of hepatic metastases, in addition to other clinical factors, may help select patients who would benefit from hepatic metastasectomy.
St Gallen Expert Consensus meetings update evidence on treatment of early breast cancer every 2 years and interpret its significance for treatment of individual patients. Such interpretation is controversial. Clinical decisions cannot, however, be postponed, and the harms of failing to tailor treatment must be balanced against those of overinterpretation. Since the ninth meeting in January 2005, an extraordinary year of progress has significantly changed the landscape in breast cancer therapy. The panel in January recommended a fundamental change in selection of adjuvant systemic therapy, giving prime attention to endocrine responsiveness. Primarily, three categories were acknowledged: endocrine responsive in which the primary treatment should be endocrine, endocrine non-responsive in which endocrine therapy should not be used, and an intermediate group for which both endocrine and other therapies should be offered. Secondarily, three risk groups were defined: low, intermediate, and high, slightly modifying the previous classification.
In June 2005, three trials, supported in December by a fourth, demonstrated the additional contribution of targeted therapy with trastuzumab in appropriately selected patients. Reports from several trials strengthened the evidence supporting the inclusion of taxanes, though controversy persists concerning their use in endocrine-responsive disease. This commentary midway between St Gallen meetings, therefore, emphasizes how new information influences algorithms for selecting adjuvant therapy in a rapidly changing environment.
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